Arysulphonyl azetidine compounds used as intermediates

ABSTRACT

Azetidine compounds of the general formula I ##STR1## wherein Ar represents a para-tolyl group and X represents a hydrogen atom, a carboxyl group or a hydroxymethyl group; their preparation from pentaerythritol via compounds of formula ##STR2## wherein Hal represents chlorine, bromine or iodine, Y represents oxygen or ##STR3## and Z represents Hal or OH, together with their use as intermediates in the preparation of 3-carboxyazetidine; also the compounds of formula ##STR4## wherein R 1  and R 2  both represent hydrogen, or together represent ##STR5##

This application is a division of application Ser. No. 569,419, filed onJan. 9, 1984.

This application relates to arylsulphonyl azetidine compounds, which areuseful as intermediates in the preparation of biologically activeazetidine compounds, together with the preparation of suchintermediates.

It is known from European patent application No. 29265 that3-carboxyazetidine and related compounds are chemical hybridisingagents, their mode of action presumably being based on their ability toproduce male sterility in plants. That application also describes aprocess for their preparation, starting from3-cyano-1-diphenylmethylazetidine, which may be prepared by methodsknown per se. Although the process described works well, it is notideally suited for large scale preparations, since the bulkydiphenylmethyl group on the nitrogen atom is removed only in the last ofa series of steps, which means that in all but the last step largeequipment is needed. Moreover, the apparent starting compounddiphenylmethylamine is relatively expensive.

It is the object of the invention therefore to provide an improvedprocess for the preparation of a 3-carboxyazetidine compound, which isachieved firstly by the provision of novel intermediates and secondly bythe provision of a process for their preparation, starting from readilyavailable compounds.

Accordingly the invention relates to 1-arylsulphonyl-3-carboxy azetidinecompounds of the general formula I: ##STR6## wherein Ar represents apara-tolyl group, and X represents a hydrogen atom, a carboxyl group ora hydroxymethyl group.

The invention also relates to a process for the preparation of acompound of formula I which comprises oxidising a compound of thegeneral formula II ##STR7## followed, when the desired product is thatwherein X is a hydrogen atom, by decarboxylation. The oxidation mayconveniently be carried out by contact with gaseous oxygen in thepresence of a catalyst, such as platinum or palladium on carbon. Theextent of the oxidation, i.e. whether the product obtained is thatwherein X represents hydroxymethyl or carboxyl is influenced by thetemperature, pH and duration of the oxidation process. Thedecarboxylation reaction, i.e. conversion of a product wherein Xrepresents carboxyl to one wherein X represents hydrogen, is suitablycarried out by heating the dicarboxyl compound for an adequate period oftime, an operation which may, where convenient, be integrated into theoxidation process whereby the starting material of formula II may bedirectly oxidised and decarboxylated to the end product of formula Iwherein X represents hydrogen.

The compound of formula II may suitably be prepared by

(i) reacting p-tosylamide with a cyclic ether of formula III. ##STR8##wherein each Hal represents a chlorine, bromine or iodine atom and Yrepresents an oxygen atom or the group ##STR9## in the presence of adehydrohalogenating agent, such as a strong base, thereby forming anazetidine derivative of formula IV ##STR10## and (ii) reacting theazetidine derivative of formula IV with an aqueous solution of strongacid.

The reaction conditions for step (i) are similar to those employed inanalogous reactions. Preferably more severe conditions are applied toachieve the necessary dehydrohalogenation when the halo atoms to beremoved are chlorine. Thus whereas sodium ethanolate in ethanol at 80°to 100° C. suffices when the halo atoms are bromine, a base likepotassium tert.butoxide in an aprotic polar solvent like dimethylsulphoxide or dimethyl formamide, at 120° C. to 150° C. is preferablyapplied when the halo atoms are chlorine.

In step (ii) the product of step (i) is converted into the compound offormula II by the action of a diluted strong acid, preferably aninorganic acid and especially H₂ SO₄. Refluxing for 1-5 hours willusually result in a quantitative reaction. In fact, the oxygencontaining ring is broken up and a propanediol moiety formed. When usinga halo acid such as (diluted) HCl, side-reactions may occur, e.g.substitution of hydroxy groups by halo atoms or even opening of thenitrogen containing ring. These side-reaction products can be convertedinto the desired product by a subsequent reaction with base, e.g.diluted NaOH.

The compounds of formula III may suitably be prepared by reactingpentaerythritol with hydrogen chloride, bromide or iodide to yield aproduct of formula: ##STR11## wherein Z represents Hal or hydroxy,followed by (i) when Z represents Hal, reaction with a base to effectdehydrohalogenation to yield the oxetane of formula III above wherein Yrepresents an oxygen atom

or

(ii) when Z represents hydroxy, reaction with acetone to form the ketalof formula III above wherein Y represents ##STR12## It will be readilyapparent that pentaerythritol is an inexpensive and readily availablecommodity product and thus represents a very convenient startingmaterial.

The first stage, reacting with HCl, HBr or HI, essentially is asubstitution of hydroxy groups by halide atoms. HCl is a slightly lesspreferred reagent, since it appears that subsequent steps proceed lessquickly with chlorinated compounds than with brominated etc. compounds.The reaction may be performed with pure, gaseous HCl, HBr or HI, or withpreviously prepared solutions thereof. However, these solutions are notrestricted to aqueous solutions, and they also include solutions ofrelated compounds in which HCl, HBr or HI may be formed in situ. Thusparticularly preferred reactant/solvent combinations are for example:aqueous HBr with acetic acid, and thionyl chloride with pyridine.

According to the reaction conditions, substitution by two or three haloatoms may be effected. Bis-halo substitution may be carried out usingHCl, HBr or HI gas according to procedures known per se, e.g. asdescribed in U.S. patent specification 3932541. Thebis-chlorosubstituted product (dichlorohydrin) is also availablecommercially. The tris-halo substitution may be effected by methodsknown for analogous compounds e.g. by boiling pentaerythritol, aceticacid and aqueous HBr and adding sulphuric acid, followed by working upthe reaction products with a chloroform extraction, or by using SOCl₂ inpyridine.

In the second step (i) the tris-halo substituted pentaerythritol, e.g.C(CH₂ Cl)₃ (CH₂ OH), is converted into a bis-halomethyloxetane by thedehydrohalogenating action of a suitable base. Suitable bases include,for example, sodium or potassium ethanolate or other alcoholates, orconveniently sodium or potassium hydroxide, dissolved in a polarsolvent, e.g. ethanol.

In the second step (ii) the bis-halo substituted pentaerythritol, e.g.C(CH₂ Br)₂ (CH₂ OH)₂, is cyclised by derivatizing the two hydroxy groupsby preparing a formal, acetal or ketal using formaldehyde, a higheraldehyde or a ketone. Preferably acetone is used to prepare a cyclicketal. Conveniently a catalytic amount of acid is present when reactingwith an aldehyde or ketone.

The compounds of formula II, and those of formula IV wherein Yrepresents the grouping ##STR13## i.e. azetidine derivatives of thegeneral formula VI ##STR14## wherein R₁ and R₂ both represent hydrogenor R₁ and R₂ together represent the group ##STR15## are novel and assuch are included within the scope of this invention.

The invention also relates to the use of the arylsulphonyl azetidines offormula I as defined above as intermediates for the preparation of3-carboxyazetidine. Such a preparation is achieved by removal of the(protective) ArSO₂ group, which may be carried out by methods known inthe art for the operation. Such methods include, e.g. hydrogenatingusing a suitable catalyst/solvent system, e.g. acetic acid, or,preferably, employing sodium in liquid ammonia. If desired, the3-carboxyazetidine may be further substituted. The substituents may beintroduced both during the foregoing series of reaction steps, orthereafter, and they could even be introduced into the3-carboxyazetidine itself.

The invention will now be illustrated further by the following Examples.NMR values are chemical shifts in ppm, relative to tetramethylsilane.

EXAMPLE 1 Preparation of 3,3-bishydroxymethyl-1-tosylazetidine via theacetone-ketal

(i) Dibromohydrin (10 g; 38 mmol) was mixed with 5 ml acetone, 0.1 g ofp-toluenesulphonic acid and 150 ml of benzene and heated under refluxwith stirring, while water was removed continuously by means of aDean-Stark trap. When the separation of water ceased, after about 2 h,the solvent was evaporated. The remaining solid (11.5 g) consisted of5,5-bisbromomethyl-2,2-dimethyl-1,3-dioxane.

(ii) The compound prepared in step (i) (11.5 g, 38 mmol) andparatoluenesulphonamide (6.5 g, 38 mmol) were mixed with 4.3 g potassiumtert.butoxide in 150 ml dimethylformamide. The mixture was heated withstirring, to 100° C. for about 5 hours. Then the mixture was cooled andevaporated in order to remove the solvent. The residue of this was takenup in 8% aqueous NaOH; the solids were filtered off and washed withdiethyl ether. After recrystallisation from CHCl₃, a white crystallinematerial (10.1 g) was obtained, consisting of pure7,7-dimethyl-2-tosyl-6,8-dioxa-2-azaspiro[3.5]nonane. This is theacetone-ketal of the title compound. The NMR spectrum in CDCl₃ was asfollows: 1.4(s, 6H), 2.5(s, 3H), 3.6(s, 4H), 3.65(s, 4H), 7.6(m, 4H).

(iii) The material obtained in (ii) was taken up in 100 ml 6.7% aqueousH₂ SO₄ and stirred for 2 hours at 100° C. Then the mixture wasneutralised with NaHCO₃ and extracted with CHCl₃. The residue wasrecrystallised from ethanol, yielding 83 g of colourless crystals,melting point 97°-99° C., being pure3,3-bishydroxymethyl-1-tosylazetidine. The NMR spectrum in CD₃ OD was asfollows: 2.5(s, 3H), 3.4(s, 4H), 3.5(s, 4H), 4.8(s, 2H), 7.6(m, 4H).

EXAMPLE 2

Example 1 was repeated using dichlorohydrin instead of dibromohydrin,and the same reaction conditions, except that in step (ii) the reactiontemperature was 150° C. The same product was obtained, though atsomewhat lower yield.

EXAMPLE 3

The last step of Examples (1) and (2) was carried out using dilute (10%)hydrochloric acid. Stirring the ketal of step (ii) at room temperaturefor 48 hours resulted in a large proportion of a ring opened productbeing formed (3-chloro-2,2-bishydroxymethyl-propanep.toluenesulphonamide). Ring closure to the desired compound wasachieved by refluxing 21/2 hours in 10% aqueous NaOH.

EXAMPLE 4 Preparation of 3,3-bishydroxymethyl-1-tosylazetidine via theoxetane

(i) A mixture of 72.0 g 90% pure pentaerythritol (529 mmol), 250 ml 47%HBr and 50 ml acetic acid was boiled for 18 hours, after which thesolvent was evaporated. The residue plus 250 ml 47% HBr and 125 ml 96%sulphuric acid was boiled for another 8 hours. After cooling, themixture was extracted with 3×100 ml CHCl₃ ; the chloroform layers werewashed with 2×100 ml H₂ O and dried over anhydrous K₂ CO₃. Filtrationand evaporation of the solvent gave 128.6 g of a dark-brown viscousresidue, which was distilled, yielding eventually 112.0 g of acolourless crystalline material and 4.4 g of a colourless oil. Analysisshowed both the oil and the crystals to contain2,2-bisbromomethyl-3-bromopropanol and the acetate thereof.

(ii) The 2,2-bisbromomethyl-3-bromopropanol and its acetate prepared instep (i) (55.4 g; 128 and 30 mmol respectively) were mixed with 10.0 gaqueous 85% KOH and 150 ml ethanol and refluxed for 1 hour. White solidswere filtered off and the filtrate was evaporated. The residue of thisevaporation was boiled with 2.5 g aqueous 25% KOH and 120 ml ethanol for11/2 hour. Again the white solids were filtered off, the filtrateevaporated and the residue boiled with the same quantities of KOH andethanol for the same time. GLC analysis now showed that conversion wascomplete. The residue was taken up in 300 ml diethyl ether, washed with100 ml water and dried over MgSO₄. After filtration and evaporation ofthe solvent, 34.0 g of a colourless liquid was obtained containing3,3-bisbromomethyloxetane.

(iii) To a solution of 70% of Na in 200 ml ethanol 48.8 gp.toluenesulphonamide (285 mmol) in 400 ml ethanol was added: a whitesolid material formed which was easily stirred in the liquid. Afteraddition of 68.8 g 3,3-bisbromomethyloxetane (241 mmol) and another 7.0g Na in 200 ml ethanol the clear solution was stirred at the refluxtemperature of 22 hours. After cooling a white solid was filtered offand the filtrate was evaporated. The residue was taken up in 300 ml 8%aqueous NaOH, the solids were filtered off and washed with 200 mldiethyl ether, after which they were recrystallised with 100 mlchloroform, yielding 43.3 g white crystalline material, being pure6-tosyl-2-oxa-6-azaspiro[3.3]heptane, melting point 143°-145° C.

(iv) The spiro-compound prepared in (iii) (13.8 g, 55 mmol) was taken upin 280 ml water, and 0.4 ml 96% sulphuric acid was slowly added thereto.The heterogeneous reaction mixture was boiled for three hours, becomingcompletely clear and colourless after about two hours. The solution wascooled, neutralised with solid NaHCO₃ and the water was evaporated. Theresidue was taken up in ethanol, filtered and the ethanol was evaporatedagain, resulting in 14.9 g of colourless crystalline material, beingpure (according to NMR and GLC) 3,3-bishydroxymethyl-1-tosylazetidine.

EXAMPLE 5

Example 4 was repeated using HCl instead of HBr in step (i). Thereafterthe reaction conditions were essentially similar, and the same productwas obtained.

EXAMPLE 6

Step (ii) of Example 4 was repeated using NaOEt as base instead of KOH,the actual procedure being as follows.

To 4.0 g Na in 100 ml ethanol 56.1 g of the product of step (i) (239mmol alcohol and 31 mmol acetate) was added and the mixture was boiledfor one hour. Another 1.0 g Na in 40 ml ethanol was added and themixture was refluxed for an hour again. GLC analysis now showed thatconversion was complete and the white solids that were filtered off,were worked up in the way of Example 4, yielding 35.2 g of a colourlessliquid containing 3,3-bisbromomethyl-oxetane. The reaction rate washigher than in Example 4, but more by-products were formed.

EXAMPLE 7

(A) Step (iii) of Example 4 was repeated using powdered sodium hydroxidein place of sodium.

To p-toluenesulphonamide (2.1 g) dissolved in dimethylsulphoxide (20 ml)was added powdered sodium hydroxide (1 g) and stirred 1/2 h at 25° C.when a milky solution was obtained. 3,3-bisbromomethyloxetane (3.0 g) indimethylsulphoxide (5 ml) was then added in one portion and the mixturestirred 15 h at 25° C. Pouring into water caused precipitation of awhite solid which was filtered off, washed with water and dried, to givethe same azaspiroheptane as obtained in Example 4(iii).

(B) Step (iii) of Example 4 was repeated using sodium hydroxide and aphase transfer catalyst in place of sodium.

3,3-bisbromomethyloxetane (10 g, 0.041 mmol) in toluene (10 ml) wasadded dropwise with stirring to a mixture of p-toluenesulphonamide (17g, 0.041 mol), tetrabutylammonium hydrogensulphate (1.4 g, 0.004 mol),toluene (50 ml) and 50% NaOH (50 ml) at 60° C. After the addition wascompleted, the mixture was heated 3 h at 80° C. when most of the solidsdissolved. Analysis (glc) showed complete disappearance of oxetane. Thereaction mixture was cooled and diluted with water when a solid formedbetween the organic and the aqueous phases. This solid was filtered off.The toluene layer was separated and the aqueous layer extracted twicewith CH₂ Cl₂. The combined toluene and CH₂ Cl₂ layers were dried andevaporated under reduced pressure to leave a white solid which wascombined with the solid filtered off. Recrystallisation from IPA/EtoHgave the same azaspiroheptane as obtained in Example 4(iii).

EXAMPLE 8

(A) Step (ii) of Example 1 was repeated using powdered sodium hydroxidein dimethyl sulphoxide in place of potassium tert.butoxide.

A mixture consisting of the dioxane obtained in Example 1(i) (5 g,0.0166 mol) p-toluenesulphonamide (2.8 g, 0.0166 mol) and powderedsodium hydroxide (1.4 g, 0.0332 mol) dissolved in dimethyl sulphoxide(100 ml) was heated 18 h at 50° C. The solvent was evaporated underreduced pressure and the product precipitated by the addition of 10%sodium hydroxide solution. This solid was filtered off, washed withwater and dried to give the same tosyl spiro nonane as that obtained inExample 1(ii).

(B) Step (ii) of Example 1 was repeated using powdered sodium hydroxideand a phase transfer catalyst in place of potassium tert.butoxide.

The dioxane obtained in Example 1(i) (3.02 g, 0.01 mol) dissolved intoluene (10 ml) was added dropwise with stirring to a mixture ofp-toluenesulphonamide (1.71 g, 0.01 mol), powdered sodium hydroxide (1.4g, 0.035 mol) potassium carbonate (1.4 g, 0.01 mol) andtetrabutylammonium bromide (0.322 g, 0.001 mol) in toluene (12 ml) keptat 50° C. After the addition was complete the mixture was stirredovernight at 120° C. After cooling the solid inorganic salts werefiltered off and washed with toluene. The filtrate and washings werethen shaken with water until neutral, dried and evaporated to leave awhite solid. Recrystallisation from ethanol/water gave the same tosylspiro nonane as that obtained in Example 1(ii).

EXAMPLE 9 Oxidation of N-tosyl-3,3-bishydroxymethyl azetidine

(A) Preparation of N-Tosyl-3-hydroxymethyl azetidine-3-carboxylic acid

Oxygen was bubbled rapidly through a stirred mixture ofN-tosyl-3,3-bishydroxymethyl azetidine (0.5 g, 0.0018 mol), sodiumbicarbonate (0.155 g, 0.0018 mol) and 5% Pt/C (0.3 g) in distilled water(10 ml) at 60° C. for 15 h. Sodium bicarbonate (0.155 g, 0.0018 mol) wasadded to maintain pH7-8 and the reaction continued a further 5 h. Aftercooling, the catalyst was filtered off, washed with water and thefiltrate acidified with 4N HCl. Extraction with ether (x3), drying andevaporating left a white solid. The catalyst was washed again with waterand the above procedure repeated to yield further solid. The whole wasrecrystallised from ethanol/water to give the title product as whitecrystals m.p. 148°-150° C.

(B) Preparation of N-Tosyl-3,3-dicarboxylazetidine

Oxygen was bubbled rapidly through a stirred mixture ofN-Tosyl-3,3-bishydroxymethyl azetidine (1.0 g, 0.0036 mol) sodiumhydroxide (0.15 g, 0.0038 mol) and 5% Pt/C (0.6 g) in distilled water(20 ml) for 18 hrs at 50°-55° C. when the pH had fallen to 7-8. Moresodium hydroxide (0.015 g, 0.0038 mol) was added and the mixture stirredanother 6 hrs. Little change was observed and fresh catalyst (0.2 g) wasadded. After a further 12 hrs more catalyst (0.4 g) was added and thereaction continued until no further change was observed (37 h). A finalfresh portion of catalyst (0.2 g) was added and the reaction mixtureallowed to stir over the weekend (72 h) at 50° C. After cooling thecatalyst was filtered off over "Celite" and the filtrate acidified with4N HCl when an immediate white precipitate formed. This precipitate wasfiltered off, washed with water and dried to give a white solid.Extraction of the aqueous filtrate plus washings with ether followed bydrying and evaporation gave further material. Recrystallisation of thecombined solids from IPA/H₂ O/EtOH gave the title product, m.p. 169° C.

EXAMPLE 10 Decarboxylation of N-tosyl-3,3-dicarboxyl azetidine

N-tosyl-3,3-dicarboxylazetidine (1 g) was warmed in an oil bath with 3drops of pyridine. At an oilbath temperature of 140° C. CO₂ evolutionand sintering started. After 1/2 h the oilbath temperature had reached160° C., the evolution of CO₂ ceased and the contents were cooled downto room temperature. Addition of a few drops of HCl converted the glassymaterial into a white crystalline material, which was N-Tosyl-azetidine3-carboxylic acid.

EXAMPLE 11 Integrated oxidation/decarboxylation

N-Tosyl-3,3-bishydroxymethyl azetidine (10 g, 0.037 mol) was suspendedin distilled water (100 ml) and 30% NaOH (3 ml) added. Dioxane (50 ml)was then added in order to obtain a homogeneous solution, followed by 1g of a 5% Pt/C catalyst. This mixture was heated under reflux with rapidstirring whilst a stream of oxygen was bubbled through at the rate of600 ml.min⁻¹. The pH of the solution was maintained at 9-12 with 30%NaOH and the course of the oxidation followed by 'H nmr. After 24 hanother 1 g of catalyst was added and after 48 h a further 2 g was addedat which point all of the starting diol had been converted. In order toachieve conversion of any intermediates, a further 1 g catalyst wasadded after 120 h. After a total reaction time of 144 h, 5 g catalysthad been added and 10 ml 30% NaOH (0.074 mol). The solution was filteredwhilst hot and the catalyst washed with dil NaOH and water. The filtrateand washings were then acidified with 4N HCl and extracted with ether(×3). The combined ether extracts were dried and evaporated to leave awhite solid which, on recrystallisation from ethyl acetate, gave N-Tosylazetidine 3-carboxylic acid.

EXAMPLE 12 Preparation of Azetidine 3-carboxylic acid

To crude N-Tosyl Azetidine 3-carboxylic acid (8.0 g, 0.0314 mol)dissolved in liquid ammonia (175 ml) at -40° C. were added small piecesof sodium metal (3.82 g, 0.165 mol) until the blue colour persisted for10 mins. Solid ammonium chloride (89 g) was then added giving acolourless solution. The ammonia was allowed to evaporate overnightunder a stream of nitrogen and the residue dissolved in water.Acidification to pH3 with 4N HCl and extraction with ether (×4) removedneutral and acidic products. The aqueous layer was evaporated todryness. This residue was dissolved in distilled water and purified bypassage over Dowex 50W-X8 (H⁺) ion-exchange resin. The column was firsteluted with water until neutral and the title product then recovered byeluting with 2N NH₄ OH.

We claim:
 1. Compounds of the formula ##STR16## wherein Ar represents apara-tolyl group, R¹ and R² each separately represents hydrogen, or R¹and R² together represent the group ##STR17## wherein each of theindicated free valence bonds is bonded to one of the indicated oxygenatoms.